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El Fil S, Uwishema O, Rizwan Ahmed A, Ratnani T, Rupani A, Mshaymesh S. Immunotherapy in gastrointestinal cancers: current strategies and future directions - a literature review. Ann Med Surg (Lond) 2025; 87:151-160. [PMID: 40109582 PMCID: PMC11918700 DOI: 10.1097/ms9.0000000000002757] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Accepted: 11/05/2024] [Indexed: 03/22/2025] Open
Abstract
Introduction The National Cancer Institute defines the disease of "cancer" as a group of disorders in which aberrant cells proliferate uncontrollably and have the potential to infiltrate neighboring tissues. It is well established that cancer remains a significant etiology contributing to worldwide mortality. Gastrointestinal (GI) neoplasms are a type of cancer that affects the digestive system and adds to the total cancer burden. Conventionally, several therapies have been employed, such as radiation and chemotherapy; nevertheless, their adverse effects have prompted the need for an improved therapeutic alternative. Immunotherapy thus became a notable medium of treatment for several malignancies, including tumors of the GI tract. Aim This comprehensive review seeks to provide insight on future directions and prospective therapies under development, as well as information regarding the present strategies utilized to mitigate one of the primary forms of cancer, GI cancer. Methods A detailed analysis of the existing literature on GI cancers has been conducted. Several databases were employed to gather this information, mainly PubMed/MEDLINE. Different aspects of the disease were considered when searching the databases to provide a comprehensive review of the current and future strategies being incorporated to mitigate the negative consequences of this disease. Results Many strategies are being used currently, and some are still under development. These comprise the usage of immune checkpoint inhibitors (ICIs), cytokine therapy, cancer vaccines, oncolytic viruses, and adoptive cell therapy. For instance, various monoclonal antibodies have been developed to inhibit the immunomodulatory effects of programmed death-1 and programmed death-1 ligand. There are also results of several clinical trials showing significant benefits and many changes are introduced to make the best of these strategies and minimize the challenges to group sizes. These challenges include overcoming the tumor's immunosuppressive environment, finding suitable predictive biomarkers, and reducing the adverse effects. Additionally, several novel immunotherapeutic approaches, such as chimeric antigen receptor T-cell (CAR-T) therapy, are being studied. In 2017, the US FDA approved the use of two CAR-T therapies, which marks a major milestone following extensive research and clinical trials. New approaches such as toll-like receptor-directed and helminth-based immunotherapies are being developed for the treatment of GI cancers as well. These therapies, along with targeted treatments, represent the future of immunotherapy in GI cancers. Conclusion Immunotherapy plays a significant role in the different types of GI cancers. However, optimizing these treatments will require overcoming barriers such as immune resistance, minimizing side effects, and improving the selection of patients through biomarkers. Continued research into these novel therapies and the mechanisms of immune modulation will be key to maximizing the therapeutic benefits of immunotherapy in the future.
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Affiliation(s)
- Serene El Fil
- Department of Research and Education, Oli Health Magazine Organization, Research and Education, Kigali, Rwanda
- Department of Natural Sciences, School of Arts and Sciences, Lebanese American University, Beirut, Lebanon
| | - Olivier Uwishema
- Department of Research and Education, Oli Health Magazine Organization, Research and Education, Kigali, Rwanda
| | - Aisha Rizwan Ahmed
- Department of Research and Education, Oli Health Magazine Organization, Research and Education, Kigali, Rwanda
- Jinnah Medical and Dental College, Karachi, Pakistan
| | - Tanya Ratnani
- Department of Research and Education, Oli Health Magazine Organization, Research and Education, Kigali, Rwanda
- Chhattisgarh Institute of Medical Sciences, Bilaspur, India
| | - Ameen Rupani
- Department of Research and Education, Oli Health Magazine Organization, Research and Education, Kigali, Rwanda
- International Higher School of Medicine, Bishkek, Kyrgyzstan
| | - Sarah Mshaymesh
- Department of Research and Education, Oli Health Magazine Organization, Research and Education, Kigali, Rwanda
- Division of Natural Sciences, Faculty of Sciences, Haigazian University, Beirut, Lebanon
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Sheykhbahaei N, Tameemi AHA, Koopaie M. Effect of short-term fasting on the cisplatin activity in human oral squamous cell carcinoma cell line HN5 and chemotherapy side effects. BMC Cancer 2024; 24:989. [PMID: 39123141 PMCID: PMC11316436 DOI: 10.1186/s12885-024-12752-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Accepted: 08/02/2024] [Indexed: 08/12/2024] Open
Abstract
BACKGROUND Ketogenic interventions like short-term fasting show potential as complementary therapies to enhance the effectiveness of chemotherapy for cancer. However, the specific effects of fasting on head and neck squamous cell carcinoma (HNSCC) cells and healthy oral mucosa cells during these treatments are not well understood. This study investigates whether short-term fasting can differentially impact HNSCC cell survival and viability compared to healthy keratinocytes while undergoing standard chemotherapy regimens. METHODS This study investigated the effects of fasting on cell viability in HN5 cell line and healthy oral keratinocyte cells. The HN5 cell line, derived from human tongue squamous cell carcinoma, and primary human keratinocytes isolated from the basal layer of gingival epithelium were divided into three groups: (1) control, (2) treated with the standard chemotherapeutic agent cisplatin, and (3) treated with cisplatin under fasting conditions achieved through 48-hour glucose restriction mimicking the blood glucose levels of fasted individuals. Cell proliferation was assessed at 48 and 72 h using the MTT assay, a colorimetric method based on mitochondrial dehydrogenase activity. Flow cytometry analysis with specific apoptosis and necrosis markers distinguished between early and late apoptotic, necrotic, and viable cells. RESULTS Cell viability in HN5 and healthy keratinocyte cells decreased in cisplatin with low glucose groups compared to cisplatin and control groups. The same results were observed for healthy keratinocyte cells; only a decrease in cell viability in cisplatin groups compared to control groups was observed, which was not statistically significant. Cell apoptosis in HN5 and healthy keratinocyte cells increased in cisplatin with low glucose groups compared to cisplatin and control groups. In healthy keratinocyte cells, the cisplatin with low glucose group showed an impressive increase in necrosis, late apoptosis, and early apoptosis and a significant decrease in live cells compared with other groups. CONCLUSION This study revealed that short-term fasting chemotherapy significantly improved HNSCC cell line apoptosis and necrosis.
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Affiliation(s)
- Nafiseh Sheykhbahaei
- Department of Oral Medicine, School of Dentistry, Tehran University of Medical Sciences, North Kargar St, Tehran, 14399-55991, Iran
| | - Ahmed Hayder Al Tameemi
- Dentist, Department of Oral Medicine, School of Dentistry, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Koopaie
- Department of Oral Medicine, School of Dentistry, Tehran University of Medical Sciences, North Kargar St, Tehran, 14399-55991, Iran.
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Goleij P, Sanaye PM, Babamohamadi M, Tabari MAK, Amirian R, Rezaee A, Mirzaei H, Kumar AP, Sethi G, Sadreddini S, Jeandet P, Khan H. Phytostilbenes in lymphoma: Focuses on the mechanistic and clinical prospects of resveratrol, pterostilbene, piceatannol, and pinosylvin. Leuk Res 2024; 138:107464. [PMID: 38422882 DOI: 10.1016/j.leukres.2024.107464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 02/05/2024] [Accepted: 02/19/2024] [Indexed: 03/02/2024]
Abstract
Lymphoma is a cancer affecting the lymphatic system that fights infections and diseases. In addition to surgery, radiotherapy, and chemotherapy, novel approaches have recently been investigated, such as phytostilbenes in treating lymphoma. Phytostilbenes are natural compounds present in various plants and have been shown to have different therapeutic effects, including anticancer properties. Resveratrol is a main phytostilbene with various derivates followed by pterostilbene and piceatannol. Studies have revealed that phytostilbenes can suppress the growth and proliferation of lymphoma cells by inducing apoptosis and inhibiting specific enzyme activity in cancer cell survival. The compounds also have antiinflammatory effects contributing to reducing lymphoma-associated inflammation. Additionally, phytostilbenes have been shown to increase the immune system's ability to fight cancer cells by activating immune cells (T-cells and natural killer cells). This review investigates the potential therapeutic effects of phytostilbenes, including resveratrol, pterostilbene, piceatannol, and pinosylvin, against lymphoma.
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Affiliation(s)
- Pouya Goleij
- Department of Genetics, Sana Institute of Higher Education, Sari, Iran; PhytoPharmacology Interest Group (PPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran; USERN Office, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Pantea Majma Sanaye
- PhytoPharmacology Interest Group (PPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran; USERN Office, Kermanshah University of Medical Sciences, Kermanshah, Iran; School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Mehregan Babamohamadi
- USERN Office, Kermanshah University of Medical Sciences, Kermanshah, Iran; Department of Biology, School of Natural Sciences, University of Tabriz, Tabriz, Iran; Stem Cell and Regenerative Medicine Innovation Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Amin Khazeei Tabari
- Student Research Committee, Mazandaran University of Medical Sciences, Sari, Iran; USERN Office, Mazandaran University of Medical Sciences, Sari, Iran
| | - Roshanak Amirian
- USERN Office, Kermanshah University of Medical Sciences, Kermanshah, Iran; Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran; Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Aryan Rezaee
- Student Research Committee, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Alan Prem Kumar
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Sarvin Sadreddini
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Philippe Jeandet
- University of Reims Champagne-Ardenne, Research Unit "Induced Resistance and Plant Bioprotection", RIBP-USC INRA 1488, Reims 51100, France
| | - Haroon Khan
- Department of Pharmacy, Faculty of Chemical and Life Sciences, Abdul Wali Khan University Mardan, Mardan 23200, Pakistan.
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Mainuddin, Kumar A, Sharma A, Sharma N. Anti-cancer Drug Targeting using Stimuli Sensitive Mesoporous Silica Nanoparticle in Colorectal Cancer. Curr Pharm Des 2024; 30:3071-3073. [PMID: 39234908 DOI: 10.2174/0113816128321020240903100601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 08/16/2024] [Accepted: 08/20/2024] [Indexed: 09/06/2024]
Affiliation(s)
- Mainuddin
- Department of Pharmaceutics, Amity Institute of Pharmacy, Amity University, Sector-125, Noida, 201313, Uttar Pradesh, India
| | - Anoop Kumar
- Department of Pharmaceutical Technology, Meerut Institute of Engineering and Technology, Meerut, 250005, India
| | - Anjana Sharma
- Department of Pharmaceutical Technology, Lloyd Institute of Management and Technology, Plot No. 11, Knowledge Park-II, Greater Noida, 201306, India
| | - Nitin Sharma
- Department of Pharmaceutics, Amity Institute of Pharmacy, Amity University, Sector-125, Noida, 201313, Uttar Pradesh, India
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Swain RM, Sanchez A, Gutierrez DA, Varela-Ramirez A, Aguilera RJ. Thiophene derivative inflicts cytotoxicity via an intrinsic apoptotic pathway on human acute lymphoblastic leukemia cells. PLoS One 2023; 18:e0295441. [PMID: 38127921 PMCID: PMC10734950 DOI: 10.1371/journal.pone.0295441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Accepted: 11/21/2023] [Indexed: 12/23/2023] Open
Abstract
In an effort to identify novel anti-cancer agents, we employed a well-established High Throughput Screening (HTS) assay to assess the cytotoxic effect of compounds within the ChemBridge DIVERSet Library on a lymphoma cell line. This screen revealed a novel thiophene, F8 (methyl 5-[(dimethylamino)carbonyl]-4-methyl-2-[(3-phenyl-2-propynoyl) amino]-3-thiophenecarboxylate), that displays anti-cancer activity on lymphoma, leukemia, and other cancer cell lines. Thiophenes and thiophene derivatives have emerged as an important class of heterocyclic compounds that have displayed favorable drug characteristics. They have been previously reported to exhibit a broad spectrum of properties and varied uses in the field of medicine. In addition, they have proven to be effective drugs in various disease scenarios. They contain anti-inflammatory, anti-anxiety, anti-psychotic, anti-microbial, anti-fungal, estrogen receptor modulating, anti-mitotic, kinase inhibiting and anti-cancer activities, rendering compounds with a thiophene a subject of significant interest in the scientific community. Compound F8 consistently induced cell death at a low micromolar range on a small panel of cancer cell lines after a 48 h period. Further investigation revealed that F8 induced phosphatidylserine externalization, reactive oxygen species generation, mitochondrial depolarization, kinase inhibition, and induces apoptosis. These findings demonstrate that F8 has promising anti-cancer activity.
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Affiliation(s)
- Risa Mia Swain
- Department of Biological Sciences, The Border Biomedical Research Center, The University of Texas at El Paso, El Paso, Texas, United States of America
- Department of Molecular and Translational Medicine, Center of Emphasis in Cancer, Paul Foster School of Medicine, Texas Tech University Health Science Center El Paso, El Paso, Texas, United States of America
| | - Anahi Sanchez
- Department of Biological Sciences, The Border Biomedical Research Center, The University of Texas at El Paso, El Paso, Texas, United States of America
| | - Denisse A. Gutierrez
- Department of Biological Sciences, The Border Biomedical Research Center, The University of Texas at El Paso, El Paso, Texas, United States of America
| | - Armando Varela-Ramirez
- Department of Biological Sciences, The Border Biomedical Research Center, The University of Texas at El Paso, El Paso, Texas, United States of America
| | - Renato J. Aguilera
- Department of Biological Sciences, The Border Biomedical Research Center, The University of Texas at El Paso, El Paso, Texas, United States of America
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Zhou M, Liang S, Liu D, Ma K, Yun K, Yao J, Peng Y, Hai L, Zhang Q, Wang Z. Manganese-Enriched Zinc Peroxide Functional Nanoparticles for Potentiating Cancer Immunotherapy. NANO LETTERS 2023; 23:10350-10359. [PMID: 37930173 DOI: 10.1021/acs.nanolett.3c02941] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/07/2023]
Abstract
Immunotherapies have shown high clinical success, however, the therapeutical efficacy is largely restrained by insufficient immune activation and an immunosuppressive microenvironment. Herein, we report tumor microenvironment (TME)-responsive manganese-enriched zinc peroxide nanoparticles (MONPs) for synergistic cancer immunotherapy by inducing the immunogenic death (ICD) of cancer cells and activating the stimulator of the interferon gene (STING) pathway. MONPs especially disassociate upon exposure to acidic tumor tissue and in situ generate •OH for the ICD effect. Moreover, Mn2+ activated the STING and synergistically induced the secretion of type I interferon and inflammatory cytokines for specific T cell responses. Meanwhile, MONPs relieved the immunosuppression of TME through decreasing Tregs and polarizing M2 macrophages to the M1 type to unleash a cascade adaptive immune response. In combination with the anti-PD-1 antibody, MONPs showed superior efficacy in inhibiting tumor growth and preventing lung metastasis. Our study demonstrates the feasibility of functional nanoparticles to amplify STING innate stimulation, showing a prominent strategy for cancer immunotherapy.
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Affiliation(s)
- Mengli Zhou
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
- Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
| | - Shuang Liang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
- Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
| | - Dan Liu
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
- Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
| | - Kongshuo Ma
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
- Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
| | - Kaiqing Yun
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
- Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
| | - Jianjun Yao
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
- Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
| | - Yuxuan Peng
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
- Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
| | - Linna Hai
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
- Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
| | - Qiang Zhang
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
| | - Zhaohui Wang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
- Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
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Roshani M, Rezaian-Isfahni A, Lotfalizadeh MH, Khassafi N, Abadi MHJN, Nejati M. Metal nanoparticles as a potential technique for the diagnosis and treatment of gastrointestinal cancer: a comprehensive review. Cancer Cell Int 2023; 23:280. [PMID: 37981671 PMCID: PMC10657605 DOI: 10.1186/s12935-023-03115-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Accepted: 10/27/2023] [Indexed: 11/21/2023] Open
Abstract
Gastrointestinal (GI) cancer is a major health problem worldwide, and current diagnostic and therapeutic approaches are often inadequate. Various metallic nanoparticles (MNPs) have been widely studied for several biomedical applications, including cancer. They may potentially overcome the challenges associated with conventional chemotherapy and significantly impact the overall survival of GI cancer patients. Functionalized MNPs with targeted ligands provide more efficient localization of tumor energy deposition, better solubility and stability, and specific targeting properties. In addition to enhanced therapeutic efficacy, MNPs are also a diagnostic tool for molecular imaging of malignant lesions, enabling non-invasive imaging or detection of tumor-specific or tumor-associated antigens. MNP-based therapeutic systems enable simultaneous stability and solubility of encapsulated drugs and regulate the delivery of therapeutic agents directly to tumor cells, which improves therapeutic efficacy and minimizes drug toxicity and leakage into normal cells. However, metal nanoparticles have been shown to have a cytotoxic effect on cells in vitro. This can be a concern when using metal nanoparticles for cancer treatment, as they may also kill healthy cells in addition to cancer cells. In this review, we provide an overview of the current state of the field, including preparation methods of MNPs, clinical applications, and advances in their use in targeted GI cancer therapy, as well as the advantages and limitations of using metal nanoparticles for the diagnosis and treatment of gastrointestinal cancer such as potential toxicity. We also discuss potential future directions and areas for further research, including the development of novel MNP-based approaches and the optimization of existing approaches.
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Affiliation(s)
- Mohammad Roshani
- Internal Medicine and Gastroenterology, Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Arya Rezaian-Isfahni
- Student Research Committee, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | | | - Negar Khassafi
- Anatomical Sciences Research Center, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Mohammad Hassan Jafari Najaf Abadi
- Research Center for Health Technology Assessment and Medical Informatics, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
| | - Majid Nejati
- Anatomical Sciences Research Center, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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Wei C, Du J, Shen Y, Wang Z, Lin Q, Chen J, Zhang F, Lin W, Wang Z, Yang Z, Ma W. Anticancer effect of involucrasin A on colorectal cancer cells by modulating the Akt/MDM2/p53 pathway. Oncol Lett 2023; 25:218. [PMID: 37153032 PMCID: PMC10157355 DOI: 10.3892/ol.2023.13804] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 02/27/2023] [Indexed: 05/09/2023] Open
Abstract
Colorectal cancer (CRC) is the second leading cause of cancer mortality worldwide; however, there is still a lack of effective clinical anti-CRC agents. Naturally-occurring compounds have been considered a potentially valuable source of new antitumorigenic agents. Involucrasin A, a novel natural molecule, was isolated from Shuteria involucrata (Wall.) Wight & Arn by our team. In the present study, the anticancer activity of involucrasin A in HCT-116 CRC cells was evaluated. Firstly, the anti-proliferative effect of involucrasin A on HCT-116 cells was analyzed by sulforhodamine B and colony formation assays. The results revealed that involucrasin A exhibited a potent inhibitory effect on HCT-116 CRC cell proliferation in vitro. Subsequently, flow cytometry and western blotting indicated that involucrasin A induced apoptosis and upregulated the expression levels of apoptosis-related proteins, such as cleaved-caspase 6 and cleaved-caspase 9, in a dose-dependent manner. Mechanistically, involucrasin A significantly inhibited the phosphorylation of Akt and murine double minute 2 homologue (MDM2), which resulted in increased intracellular levels of p53. This was reversed by exogenous expression of the constitutively active form of Akt. Similarly, either knocking out p53 or knocking down Bax abrogated involucrasin A-induced proliferation inhibition and apoptosis. Together, the present study indicated that involucrasin A exerts antitumorigenic activities via modulating the Akt/MDM2/p53 pathway in HCT-116 CRC cells, and it is worthy of further exploration in preclinical and clinical trials.
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Affiliation(s)
- Chengming Wei
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, SAR 999078, P.R. China
| | - Jingjing Du
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, SAR 999078, P.R. China
| | - Yunfu Shen
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, SAR 999078, P.R. China
| | - Zi Wang
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, SAR 999078, P.R. China
| | - Qianyu Lin
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, SAR 999078, P.R. China
| | - Junhe Chen
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, SAR 999078, P.R. China
| | - Fuming Zhang
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, SAR 999078, P.R. China
| | - Wanjun Lin
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, SAR 999078, P.R. China
| | - Zhibin Wang
- Faculty of Pharmaceutical Sciences, Shenzhen Institute of Advanced Technology Chinese Academy of Sciences, Shenzhen, Guangdong 518000, P.R. China
| | - Zhuya Yang
- School of Traditional Chinese Medicine, Yunnan University of Traditional Chinese Medicine, Kunming, Yunnan 650500, P.R. China
- Correspondence to: Professor Zhuya Yang, School of Traditional Chinese Medicine, Yunnan University of Traditional Chinese Medicine, 1076 Yuhua Road, Chenggong, Kunming, Yunnan 650500, P.R. China, E-mail:
| | - Wenzhe Ma
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, SAR 999078, P.R. China
- Professor Wenzhe Ma, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wailong, Block H701, Macau, SAR 999078, P.R. China, E-mail:
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Zhao N, Song Y, Xie X, Zhu Z, Duan C, Nong C, Wang H, Bao R. Synthetic biology-inspired cell engineering in diagnosis, treatment, and drug development. Signal Transduct Target Ther 2023; 8:112. [PMID: 36906608 PMCID: PMC10007681 DOI: 10.1038/s41392-023-01375-x] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 01/31/2023] [Accepted: 02/15/2023] [Indexed: 03/13/2023] Open
Abstract
The fast-developing synthetic biology (SB) has provided many genetic tools to reprogram and engineer cells for improved performance, novel functions, and diverse applications. Such cell engineering resources can play a critical role in the research and development of novel therapeutics. However, there are certain limitations and challenges in applying genetically engineered cells in clinical practice. This literature review updates the recent advances in biomedical applications, including diagnosis, treatment, and drug development, of SB-inspired cell engineering. It describes technologies and relevant examples in a clinical and experimental setup that may significantly impact the biomedicine field. At last, this review concludes the results with future directions to optimize the performances of synthetic gene circuits to regulate the therapeutic activities of cell-based tools in specific diseases.
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Affiliation(s)
- Ninglin Zhao
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Yingjie Song
- College of Life Science, Sichuan Normal University, Chengdu, China
| | - Xiangqian Xie
- State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center of Nanjing University, Jiangsu Key Laboratory of Advanced Organic Materials, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China
| | - Ziqi Zhu
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Chenxi Duan
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Cheng Nong
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Huan Wang
- State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center of Nanjing University, Jiangsu Key Laboratory of Advanced Organic Materials, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China.
| | - Rui Bao
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China.
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Giordani C, Russo S, Torrisi C, Morante S, Castelli F, Sarpietro MG. A Thermodynamic Study on the Interaction between RH-23 Peptide and DMPC-Based Biomembrane Models. MEMBRANES 2022; 12:1282. [PMID: 36557189 PMCID: PMC9781852 DOI: 10.3390/membranes12121282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 12/12/2022] [Accepted: 12/15/2022] [Indexed: 06/17/2023]
Abstract
Investigation of the interaction between drugs and biomembrane models, as a strategy to study and eventually improve drug/substrate interactions, is a crucial factor in preliminary screening. Synthesized peptides represent a source of potential anticancer and theragnostic drugs. In this study, we investigated the interaction of a novel synthesized peptide, called RH-23, with a simplified dimyristoylphosphatidylcholine (DMPC) model of the cellular membrane. The interaction of RH-23 with DMPC, organized either in multilamellar vesicles (MLVs) and in Langmuir-Blodgett (LB) monolayers, was assessed using thermodynamic techniques, namely differential scanning calorimetry (DSC) and LB. The calorimetric evaluations showed that RH-23 inserted into MLVs, causing a stabilization of the phospholipid gel phase that increased with the molar fraction of RH-23. Interplay with LB monolayers revealed that RH-23 interacted with DMPC molecules. This work represents the first experimental thermodynamic study on the interaction between RH-23 and a simplified model of the lipid membrane, thus providing a basis for further evaluations of the effect of RH-23 on biological membranes and its therapeutic/diagnostic potential.
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Affiliation(s)
- Cristiano Giordani
- Grupo Productos Naturales Marinos, Facultad de Ciencias Farmacéuticas y Alimentarias, Universidad de Antioquia, Calle 70 No. 52-21, Medellín 050010, Colombia
- Instituto de Física, Universidad de Antioquia, Calle 70 No. 52-21, Medellín 050010, Colombia
| | - Stefano Russo
- Dipartimento di Scienze del Farmaco e della Salute, Università degli Studi di Catania, Viale A. Doria 6, 95125 Catania, Italy
| | - Cristina Torrisi
- Dipartimento di Scienze del Farmaco e della Salute, Università degli Studi di Catania, Viale A. Doria 6, 95125 Catania, Italy
| | - Silvia Morante
- Dipartimento di Fisica, University of Rome Tor Vergata and Istituto Nazionale di Fisica Nucleare (INFN), Via della Ricerca Scientifica 1, 00133 Roma, Italy
| | - Francesco Castelli
- Dipartimento di Scienze del Farmaco e della Salute, Università degli Studi di Catania, Viale A. Doria 6, 95125 Catania, Italy
| | - Maria Grazia Sarpietro
- Dipartimento di Scienze del Farmaco e della Salute, Università degli Studi di Catania, Viale A. Doria 6, 95125 Catania, Italy
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11
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Busa P, Kankala RK, Deng JP, Liu CL, Lee CH. Conquering Cancer Multi-Drug Resistance Using Curcumin and Cisplatin Prodrug-Encapsulated Mesoporous Silica Nanoparticles for Synergistic Chemo- and Photodynamic Therapies. NANOMATERIALS (BASEL, SWITZERLAND) 2022; 12:3693. [PMID: 36296885 PMCID: PMC9609490 DOI: 10.3390/nano12203693] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 10/16/2022] [Accepted: 10/18/2022] [Indexed: 06/16/2023]
Abstract
Recently, the development of anti-cancer approaches using different physical or chemical pathways has shifted from monotherapy to synergistic therapy, which can enhance therapeutic effects. As a result, enormous efforts have been devoted to developing various delivery systems encapsulated with dual agents for synergistic effects and to combat cancer cells acquired drug resistance. In this study, we show how to make Institute of Bioengineering and Nanotechnology (IBN)-1-based mesoporous silica nanoparticles (MSNs) for multifunctional drug delivery to overcome drug resistance cancer therapy. Initially, curcumin (Cur)-embedded IBN-1 nanocomposites (IBN-1-Cur) are synthesized in a simple one-pot co-condensation and then immobilized with the prodrug of Cisplatin (CP) on the carboxylate-modified surface (IBN-1-Cur-CP) to achieve photodynamic therapy (PDT) and chemotherapy in one platform, respectively, in the fight against multidrug resistance (MDR) of MES-SA/DX5 cancer cells. The Pluronic F127 triblock copolymer, as the structure-directing agent, in nanoparticles acts as a p-glycoprotein (p-gp) inhibitor. These designed hybrid nanocomposites with excellent structural properties are efficiently internalized by the endocytosis and successfully deliver Cur and CP molecules into the cytosol. Furthermore, the presence of Cur photosensitizer in the nanochannels of MSNs resulted in increased levels of cellular reactive oxygen species (ROS) under light irradiation. Thus, IBN-1-Cur-CP showed excellent anti-cancer therapy in the face of MES-SA/DX5 resistance cancer cells, owing to the synergistic effects of chemo- and photodynamic treatment.
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Affiliation(s)
- Prabhakar Busa
- Department of Life Science, National Dong Hwa University, Hualien 97401, Taiwan
| | - Ranjith Kumar Kankala
- Department of Life Science, National Dong Hwa University, Hualien 97401, Taiwan
- College of Chemical Engineering, Huaqiao University, Xiamen 361021, China
| | - Jin-Pei Deng
- Department of Chemistry, Tamkang University, New Taipei City 251, Taiwan
| | - Chen-Lun Liu
- Department of Life Science, National Dong Hwa University, Hualien 97401, Taiwan
| | - Chia-Hung Lee
- Department of Life Science, National Dong Hwa University, Hualien 97401, Taiwan
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12
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Ding YN, Xue M, Tang QS, Wang LJ, Ding HY, Li H, Gao CC, Yu WP. Immunotherapy-based novel nanoparticles in the treatment of gastrointestinal cancer: Trends and challenges. World J Gastroenterol 2022; 28:5403-5419. [PMID: 36312831 PMCID: PMC9611702 DOI: 10.3748/wjg.v28.i37.5403] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 08/27/2022] [Accepted: 09/15/2022] [Indexed: 02/06/2023] Open
Abstract
Gastrointestinal cancer (GIC) is the most common cancer with a poor prognosis. Currently, surgery is the main treatment for GIC. However, the high rate of postoperative recurrence leads to a low five-year survival rate. In recent years, immunotherapy has received much attention. As the only immunotherapy drugs approved by the Food and Drug Administration (FDA), immune checkpoint blockade (ICB) drugs have great potential in cancer therapy. Nevertheless, the efficacy of ICB treatment is greatly limited by the low immunogenicity and immunosuppressive microenvironment of GIC. Therefore, the targets of immunotherapy have expanded from ICB to increasing tumor immunogenicity, increasing the recruitment and maturation of immune cells and reducing the proportion of inhibitory immune cells, such as M2-like macrophages, regulatory T cells and myeloid-derived suppressor cells. Moreover, with the development of nanotechnology, a variety of nanoparticles have been approved by the FDA for clinical therapy, so novel nanodrug delivery systems have become a research focus for anticancer therapy. In this review, we summarize recent advances in the application of immunotherapy-based nanoparticles in GICs, such as gastric cancer, hepatocellular carcinoma, colorectal cancer and pancreatic cancer, and described the existing challenges and future trends.
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Affiliation(s)
- Yi-Nan Ding
- Department of Pathophysiology, College of Medicine, Southeast University, Nanjing 210000, Jiangsu Province, China
| | - Ming Xue
- Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210000, Jiangsu Province, China
| | - Qiu-Sha Tang
- Department of Pathophysiology, College of Medicine, Southeast University, Nanjing 210000, Jiangsu Province, China
| | - Li-Jun Wang
- Department of Pathophysiology, College of Medicine, Southeast University, Nanjing 210000, Jiangsu Province, China
| | - Hui-Yan Ding
- Department of Pathophysiology, College of Medicine, Southeast University, Nanjing 210000, Jiangsu Province, China
| | - Han Li
- Department of Tuberculosis, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing 210000, Jiangsu Province, China
| | - Cheng-Cheng Gao
- Department of Radiology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
| | - Wei-Ping Yu
- Medical School, Southeast University, Nanjing 210009, Jiangsu Province, China
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13
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Marin JJG, Monte MJ, Macias RIR, Romero MR, Herraez E, Asensio M, Ortiz-Rivero S, Cives-Losada C, Di Giacomo S, Gonzalez-Gallego J, Mauriz JL, Efferth T, Briz O. Expression of Chemoresistance-Associated ABC Proteins in Hepatobiliary, Pancreatic and Gastrointestinal Cancers. Cancers (Basel) 2022; 14:cancers14143524. [PMID: 35884584 PMCID: PMC9320734 DOI: 10.3390/cancers14143524] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 07/14/2022] [Accepted: 07/14/2022] [Indexed: 11/16/2022] Open
Abstract
Simple Summary One-third of the approximately 10 million deaths yearly caused by cancer worldwide are due to hepatobiliary, pancreatic, and gastrointestinal tumors. One primary reason for this high mortality is the lack of response of these cancers to pharmacological treatment. More than 100 genes have been identified as responsible for seven mechanisms of chemoresistance, but only a few of them play a critical role. These include ABC proteins (mainly MDR1, MRP1-6, and BCRP), whose expression pattern greatly determines the individual sensitivity of each tumor to pharmacotherapy. Abstract Hepatobiliary, pancreatic, and gastrointestinal cancers account for 36% of the ten million deaths caused by cancer worldwide every year. The two main reasons for this high mortality are their late diagnosis and their high refractoriness to pharmacological treatments, regardless of whether these are based on classical chemotherapeutic agents, targeted drugs, or newer immunomodulators. Mechanisms of chemoresistance (MOC) defining the multidrug resistance (MDR) phenotype of each tumor depend on the synergic function of proteins encoded by more than one hundred genes classified into seven groups (MOC1-7). Among them, the efflux of active agents from cancer cells across the plasma membrane caused by members of the superfamily of ATP-binding cassette (ABC) proteins (MOC-1b) plays a crucial role in determining tumor MDR. Although seven families of human ABC proteins are known, only a few pumps (mainly MDR1, MRP1-6, and BCRP) have been associated with reducing drug content and hence inducing chemoresistance in hepatobiliary, pancreatic, and gastrointestinal cancer cells. The present descriptive review, which compiles the updated information on the expression of these ABC proteins, will be helpful because there is still some confusion on the actual relevance of these pumps in response to pharmacological regimens currently used in treating these cancers. Moreover, we aim to define the MOC pattern on a tumor-by-tumor basis, even in a dynamic way, because it can vary during tumor progression and in response to chemotherapy. This information is indispensable for developing novel strategies for sensitization.
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Affiliation(s)
- Jose J. G. Marin
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (M.J.M.); (R.I.R.M.); (M.R.R.); (E.H.); (M.A.); (S.O.-R.); (C.C.-L.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain; (J.G.-G.); (J.L.M.)
- Correspondence: (J.J.G.M.); (O.B.); Tel.: +34-663182872 (J.J.G.M.); +34-663056225 (O.B.)
| | - Maria J. Monte
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (M.J.M.); (R.I.R.M.); (M.R.R.); (E.H.); (M.A.); (S.O.-R.); (C.C.-L.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain; (J.G.-G.); (J.L.M.)
| | - Rocio I. R. Macias
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (M.J.M.); (R.I.R.M.); (M.R.R.); (E.H.); (M.A.); (S.O.-R.); (C.C.-L.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain; (J.G.-G.); (J.L.M.)
| | - Marta R. Romero
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (M.J.M.); (R.I.R.M.); (M.R.R.); (E.H.); (M.A.); (S.O.-R.); (C.C.-L.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain; (J.G.-G.); (J.L.M.)
| | - Elisa Herraez
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (M.J.M.); (R.I.R.M.); (M.R.R.); (E.H.); (M.A.); (S.O.-R.); (C.C.-L.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain; (J.G.-G.); (J.L.M.)
| | - Maitane Asensio
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (M.J.M.); (R.I.R.M.); (M.R.R.); (E.H.); (M.A.); (S.O.-R.); (C.C.-L.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain; (J.G.-G.); (J.L.M.)
| | - Sara Ortiz-Rivero
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (M.J.M.); (R.I.R.M.); (M.R.R.); (E.H.); (M.A.); (S.O.-R.); (C.C.-L.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain; (J.G.-G.); (J.L.M.)
| | - Candela Cives-Losada
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (M.J.M.); (R.I.R.M.); (M.R.R.); (E.H.); (M.A.); (S.O.-R.); (C.C.-L.)
| | - Silvia Di Giacomo
- Department of Physiology and Pharmacology “Vittorio Erspamer”, Sapienza University of Rome, 00185 Rome, Italy;
| | - Javier Gonzalez-Gallego
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain; (J.G.-G.); (J.L.M.)
- Institute of Biomedicine (IBIOMED), University of León, Campus of Vegazana s/n, 24071 Leon, Spain
| | - Jose L. Mauriz
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain; (J.G.-G.); (J.L.M.)
- Institute of Biomedicine (IBIOMED), University of León, Campus of Vegazana s/n, 24071 Leon, Spain
| | - Thomas Efferth
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany;
| | - Oscar Briz
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (M.J.M.); (R.I.R.M.); (M.R.R.); (E.H.); (M.A.); (S.O.-R.); (C.C.-L.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain; (J.G.-G.); (J.L.M.)
- Correspondence: (J.J.G.M.); (O.B.); Tel.: +34-663182872 (J.J.G.M.); +34-663056225 (O.B.)
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Singh R, Sharma A, Saji J, Umapathi A, Kumar S, Daima HK. Smart nanomaterials for cancer diagnosis and treatment. NANO CONVERGENCE 2022; 9:21. [PMID: 35569081 PMCID: PMC9108129 DOI: 10.1186/s40580-022-00313-x] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 04/26/2022] [Indexed: 05/14/2023]
Abstract
Innovations in nanomedicine has guided the improved outcomes for cancer diagnosis and therapy. However, frequent use of nanomaterials remains challenging due to specific limitations like non-targeted distribution causing low signal-to-noise ratio for diagnostics, complex fabrication, reduced-biocompatibility, decreased photostability, and systemic toxicity of nanomaterials within the body. Thus, better nanomaterial-systems with controlled physicochemical and biological properties, form the need of the hour. In this context, smart nanomaterials serve as promising solution, as they can be activated under specific exogenous or endogenous stimuli such as pH, temperature, enzymes, or a particular biological molecule. The properties of smart nanomaterials make them ideal candidates for various applications like biosensors, controlled drug release, and treatment of various diseases. Recently, smart nanomaterial-based cancer theranostic approaches have been developed, and they are displaying better selectivity and sensitivity with reduced side-effects in comparison to conventional methods. In cancer therapy, the smart nanomaterials-system only activates in response to tumor microenvironment (TME) and remains in deactivated state in normal cells, which further reduces the side-effects and systemic toxicities. Thus, the present review aims to describe the stimulus-based classification of smart nanomaterials, tumor microenvironment-responsive behaviour, and their up-to-date applications in cancer theranostics. Besides, present review addresses the development of various smart nanomaterials and their advantages for diagnosing and treating cancer. Here, we also discuss about the drug targeting and sustained drug release from nanocarriers, and different types of nanomaterials which have been engineered for this intent. Additionally, the present challenges and prospects of nanomaterials in effective cancer diagnosis and therapeutics have been discussed.
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Affiliation(s)
- Ragini Singh
- College of Agronomy, Liaocheng University, Liaocheng, 252059, Shandong, China.
| | - Ayush Sharma
- Amity Center for Nanobiotechnology and Nanomedicine (ACNN), Amity Institute of Biotechnology, Amity University Rajasthan, Jaipur, 303002, Rajasthan, India
| | - Joel Saji
- Amity Center for Nanobiotechnology and Nanomedicine (ACNN), Amity Institute of Biotechnology, Amity University Rajasthan, Jaipur, 303002, Rajasthan, India
| | - Akhela Umapathi
- Amity Center for Nanobiotechnology and Nanomedicine (ACNN), Amity Institute of Biotechnology, Amity University Rajasthan, Jaipur, 303002, Rajasthan, India
| | - Santosh Kumar
- Shandong Key Laboratory of Optical Communication Science and Technology, School of Physics Science and Information Technology, Liaocheng University, Liaocheng, 252059, Shandong, China
| | - Hemant Kumar Daima
- Amity Center for Nanobiotechnology and Nanomedicine (ACNN), Amity Institute of Biotechnology, Amity University Rajasthan, Jaipur, 303002, Rajasthan, India.
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15
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Sonju JJ, Dahal A, Singh SS, Gu X, Johnson WD, Muthumula CMR, Meyer SA, Jois SD. A pH-sensitive liposome formulation of a peptidomimetic-Dox conjugate for targeting HER2 + cancer. Int J Pharm 2022; 612:121364. [PMID: 34896567 PMCID: PMC8751737 DOI: 10.1016/j.ijpharm.2021.121364] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 12/03/2021] [Accepted: 12/05/2021] [Indexed: 02/06/2023]
Abstract
Cancer treatment faces the challenge of selective delivery of the cytotoxic drug to the desired site of action to minimize undesired side effects. The liposomal formulation containing targeting ligand conjugated cytotoxic drug can be an effective approach to specifically deliver chemotherapeutic drugs to cancer cells that overexpress a particular cell surface receptor. This research focuses on the in vitro and in vivo studies of a peptidomimetic ligand attached doxorubicin for the HER2 positive lung and breast cancer cells transported by a pH-dependent liposomal formulation system for the enhancement of targeted anticancer treatment. The selected pH-sensitive liposome formulation showed effective pH-dependent delivery of peptidomimetic-doxorubicin conjugate at lower pH conditions mimicking tumor microenvironment (pH-6.5) compared to normal physiological conditions (pH 7.4), leading to the improvement of cell uptake. In vivo results revealed the site-specific delivery of the formulation and enhanced antitumor activity with reduced toxicity compared to the free doxorubicin (Free Dox). The results suggested that the targeting ligand conjugated cytotoxic drug with the pH-sensitive liposomal formulation is a promising approach to chemotherapy.
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Affiliation(s)
- Jafrin Jobayer Sonju
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71201
| | - Achyut Dahal
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71201
| | - Sitanshu S. Singh
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71201
| | - Xin Gu
- Department of Pathology, Louisiana State University Health Sciences Center, 1501 Kings Hwy, Shreveport, LA, 71103, USA
| | - William D. Johnson
- Biostatistics Department, Pennington Biomedical Research Center, Baton Rouge, LA 70808
| | - Chandra Mohan Reddy Muthumula
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71201
| | - Sharon A Meyer
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71201
| | - Seetharama D. Jois
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71201,To whom correspondence should be addressed: Seetharama D. Jois, Professor of Medicinal Chemistry, School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, 1800 Bienville Drive, Monroe LA 71201 USA Tel: 318-342-1993; Fax: 318-342-1737;
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16
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Synthesis, characterization, and biological evaluation of doxorubicin containing silk fibroin micro- and nanoparticles. J INDIAN CHEM SOC 2021. [DOI: 10.1016/j.jics.2021.100161] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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17
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Zalloum WA, Zalloum N. Comparative QM/MM Molecular Dynamics and Umbrella Sampling Simulations: Interaction of the Zinc-Bound Intermediate Gem-Diolate Trapoxin A Inhibitor and Acetyl-l-lysine Substrate with Histone Deacetylase 8. J Phys Chem B 2021; 125:5321-5337. [PMID: 33998791 DOI: 10.1021/acs.jpcb.1c01696] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Targeting the genetic material without destruction is a priority to develop safe anticancer drugs. Histone deacetylase 8 (HDAC8), which is proved to be involved in carcinogenesis, is an enzyme associated with the chromatin for post-translational deacetylation of acetylated lysine. In this study, HDAC8 co-crystallized with the intermediate state tetrapeptide Trapoxin A (TA) inhibitor and the holoenzyme are utilized to find their conformational ensembles. Furthermore, the co-crystallized intermediate gem-diolate TA was used to find optimum interactions with the active site residues by conventional molecular dynamics (MD) simulation and QM/MM umbrella sampling. Finally, the intermediate state of the acetyl-l-lysine substrate was explored by QM/MM steered MD and compared to the binding of the intermediate state of the inhibitor. This research showed that HDAC8 is flexible and exists in conformational ensembles in its holoenzyme state. Binding of the intermediate state TA stabilizes its conformation. The optimum binding to the active site of HDAC8 for structures of gem-diolate TA (intermediate state) and acetyl-l-lysine (intermediate state) was determined according to the corresponding energy profiles. The use of these models will aid in the design of potentially reversible, potent, and selective inhibitors of HDAC8 for cancer treatment.
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Affiliation(s)
- Waleed A Zalloum
- Department of Pharmacy, Faculty of Health Science, American University of Madaba, P.O. Box 2882, Amman 11821, Jordan
| | - Needa Zalloum
- Department of Biopharmaceutics and Clinical Pharmacy, Faculty of Pharmacy, University of Jordan, Amman 11942, Jordan
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18
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Abdel-Rahman SA, Wafa EI, Ebeid K, Geary SM, Naguib YW, El-Damasy AK, Salem AK. Thiophene derivative-loaded nanoparticles mediate anticancer activity through the inhibition of kinases and microtubule assembly. ADVANCED THERAPEUTICS 2021; 4. [PMID: 34423112 DOI: 10.1002/adtp.202100058] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Different tetrahydrobenzo[b]thiophene derivatives were explored as new tubulin polymerization destabilizers to arrest tumor cell mitosis. A series of compounds incorporating the tetrahydrobenzo[b]thiophene scaffold were synthesized, and their biological activities were investigated. The cytotoxicity of each of the synthesized compounds was assessed against a range of cell lines. Specifically, the benzyl urea tetrahydrobenzo[b]thiophene derivative, 1-benzyl-3-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)urea (BU17), was identified as the most potent compound with broad-spectrum antitumor activity against several cancer cell lines. The potential mechanism(s) of action were investigated where dose-dependent G2/M accumulation and A549 cell cycle arrest were detected. Additionally, A549 cells treated with BU17 expressed enhanced levels of caspase 3 and 9, indicating the induction of apoptosis. Furthermore, it was found that BU17 inhibits WEE1 kinase and targets tubulin by blocking its polymerization. BU17 was also formulated into PLGA nanoparticles, and it was demonstrated that BU17-loaded nanoparticles could significantly enhance antitumor activity compared to the soluble counterpart.
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Affiliation(s)
- Somaya A Abdel-Rahman
- Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA 52242, USA.,Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Emad I Wafa
- Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA 52242, USA
| | - Kareem Ebeid
- Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA 52242, USA.,Department of Pharmaceutics, Faculty of Pharmacy, Minia University, Minia 61519, Egypt.,Department of Pharmaceutics, Faculty of Pharmacy, Deraya University, New Minia City, Minia, 61519 Egypt
| | - Sean M Geary
- Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA 52242, USA
| | - Youssef W Naguib
- Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA 52242, USA.,Department of Pharmaceutics, Faculty of Pharmacy, Minia University, Minia 61519, Egypt.,Department of Pharmaceutics, Faculty of Pharmacy, Deraya University, New Minia City, Minia, 61519 Egypt
| | - Ashraf K El-Damasy
- Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Aliasger K Salem
- Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA 52242, USA.,Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA
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Naik H, Sonju JJ, Singh S, Chatzistamou I, Shrestha L, Gauthier T, Jois S. Lipidated Peptidomimetic Ligand-Functionalized HER2 Targeted Liposome as Nano-Carrier Designed for Doxorubicin Delivery in Cancer Therapy. Pharmaceuticals (Basel) 2021; 14:221. [PMID: 33800723 PMCID: PMC8002094 DOI: 10.3390/ph14030221] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 03/02/2021] [Accepted: 03/03/2021] [Indexed: 12/13/2022] Open
Abstract
The therapeutic index of chemotherapeutic agents can be improved by the use of nano-carrier-mediated chemotherapeutic delivery. Ligand-targeted drug delivery can be used to achieve selective and specific delivery of chemotherapeutic agents to cancer cells. In this study, we prepared a peptidomimetic conjugate (SA-5)-tagged doxorubicin (Dox) incorporated liposome (LP) formulation (SA-5-Dox-LP) to evaluate the targeted delivery potential of SA-5 in human epidermal growth factor receptor-2 (HER2) overexpressed non-small-cell lung cancer (NSCLC) and breast cancer cell lines. The liposome was prepared using thin lipid film hydration and was characterized for particle size, encapsulation efficiency, cell viability, and targeted cellular uptake. In vivo evaluation of the liposomal formulation was performed in a mice model of NSCLC. The cell viability studies revealed that targeted SA-5-Dox-LP showed better antiproliferative activity than non-targeted Dox liposomes (Dox-LP). HER2-targeted liposome delivery showed selective cellular uptake compared to non-targeted liposomes on cancer cells. In vitro drug release studies indicated that Dox was released slowly from the formulations over 24 h, and there was no difference in Dox release between Dox-LP formulation and SA-5-Dox-LP formulation. In vivo studies in an NSCLC model of mice indicated that SA-5-Dox-LP could reduce the lung tumors significantly compared to vehicle control and Dox. In conclusion, this study demonstrated that the SA-5-Dox-LP liposome has the potential to increase therapeutic efficiency and targeted delivery of Dox in HER2 overexpressing cancer.
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Affiliation(s)
- Himgauri Naik
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71201, USA; (H.N.); (J.J.S.); (S.S.); (L.S.)
| | - Jafrin Jobayer Sonju
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71201, USA; (H.N.); (J.J.S.); (S.S.); (L.S.)
| | - Sitanshu Singh
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71201, USA; (H.N.); (J.J.S.); (S.S.); (L.S.)
| | - Ioulia Chatzistamou
- Department of Pathology, Microbiology & Immunology (PMI), School of Medicine, USC, SC 6439 Garners Ferry Rd, Columbia, SC 29208, USA;
| | - Leeza Shrestha
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71201, USA; (H.N.); (J.J.S.); (S.S.); (L.S.)
| | - Ted Gauthier
- Biotechnology Laboratory, LSU AgCenter, Louisiana State University, Baton Rouge, LA 70803, USA;
| | - Seetharama Jois
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71201, USA; (H.N.); (J.J.S.); (S.S.); (L.S.)
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20
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Mulford AJ, Wing C, Dolan ME, Wheeler HE. Genetically regulated expression underlies cellular sensitivity to chemotherapy in diverse populations. Hum Mol Genet 2021; 30:305-317. [PMID: 33575800 DOI: 10.1093/hmg/ddab029] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 01/12/2021] [Accepted: 01/19/2021] [Indexed: 11/14/2022] Open
Abstract
Most cancer chemotherapeutic agents are ineffective in a subset of patients; thus, it is important to consider the role of genetic variation in drug response. Lymphoblastoid cell lines (LCLs) in 1000 Genomes Project populations of diverse ancestries are a useful model for determining how genetic factors impact the variation in cytotoxicity. In our study, LCLs from three 1000 Genomes Project populations of diverse ancestries were previously treated with increasing concentrations of eight chemotherapeutic drugs, and cell growth inhibition was measured at each dose with half-maximal inhibitory concentration (IC50) or area under the dose-response curve (AUC) as our phenotype for each drug. We conducted both genome-wide association studies (GWAS) and transcriptome-wide association studies (TWAS) within and across ancestral populations. We identified four unique loci in GWAS and three genes in TWAS to be significantly associated with the chemotherapy-induced cytotoxicity within and across ancestral populations. In the etoposide TWAS, increased STARD5 predicted expression associated with decreased etoposide IC50 (P = 8.5 × 10-8). Functional studies in A549, a lung cancer cell line, revealed that knockdown of STARD5 expression resulted in the decreased sensitivity to etoposide following exposure for 72 (P = 0.033) and 96 h (P = 0.0001). By identifying loci and genes associated with cytotoxicity across ancestral populations, we strive to understand the genetic factors impacting the effectiveness of chemotherapy drugs and to contribute to the development of future cancer treatment.
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Affiliation(s)
- Ashley J Mulford
- Department of Biology, Loyola University Chicago, Chicago, IL 60660, USA.,Program in Bioinformatics, Loyola University Chicago, Chicago, IL 60660, USA
| | - Claudia Wing
- Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA
| | - M Eileen Dolan
- Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA
| | - Heather E Wheeler
- Department of Biology, Loyola University Chicago, Chicago, IL 60660, USA.,Program in Bioinformatics, Loyola University Chicago, Chicago, IL 60660, USA
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Cellular Mechanisms Accounting for the Refractoriness of Colorectal Carcinoma to Pharmacological Treatment. Cancers (Basel) 2020; 12:cancers12092605. [PMID: 32933095 PMCID: PMC7563523 DOI: 10.3390/cancers12092605] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 09/07/2020] [Accepted: 09/09/2020] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Colorectal cancer (CRC) causes a high number (more than 800,000) of deaths worldwide each year. Better methods for early diagnosis and the development of strategies to enhance the efficacy of the therapeutic approaches used to complement or substitute surgical removal of the tumor are urgently needed. Currently available pharmacological armamentarium provides very moderate benefits to patients due to the high resistance of tumor cells to respond to anticancer drugs. The present review summarizes and classifies into seven groups the cellular and molecular mechanisms of chemoresistance (MOC) accounting for the failure of CRC response to the pharmacological treatment. Abstract The unsatisfactory response of colorectal cancer (CRC) to pharmacological treatment contributes to the substantial global health burden caused by this disease. Over the last few decades, CRC has become the cause of more than 800,000 deaths per year. The reason is a combination of two factors: (i) the late cancer detection, which is being partially solved by the implementation of mass screening of adults over age 50, permitting earlier diagnosis and treatment; (ii) the inadequate response of advanced unresectable tumors (i.e., stages III and IV) to pharmacological therapy. The latter is due to the existence of complex mechanisms of chemoresistance (MOCs) that interact and synergize with each other, rendering CRC cells strongly refractory to the available pharmacological regimens based on conventional chemotherapy, such as pyrimidine analogs (5-fluorouracil, capecitabine, trifluridine, and tipiracil), oxaliplatin, and irinotecan, as well as drugs targeted toward tyrosine kinase receptors (regorafenib, aflibercept, bevacizumab, cetuximab, panitumumab, and ramucirumab), and, more recently, immune checkpoint inhibitors (nivolumab, ipilimumab, and pembrolizumab). In the present review, we have inventoried the genes involved in the lack of CRC response to pharmacological treatment, classifying them into seven groups (from MOC-1 to MOC-7) according to functional criteria to identify cancer cell weaknesses. This classification will be useful to pave the way for developing sensitizing tools consisting of (i) new agents to be co-administered with the active drug; (ii) pharmacological approaches, such as drug encapsulation (e.g., into labeled liposomes or exosomes); (iii) gene therapy interventions aimed at restoring the impaired function of some proteins (e.g., uptake transporters and tumor suppressors) or abolishing that of others (such as export pumps and oncogenes).
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Abdel-Rahman SA, El-Damasy AK, Hassan GS, Wafa EI, Geary SM, Maarouf AR, Salem AK. Cyclohepta[ b]thiophenes as Potential Antiproliferative Agents: Design, Synthesis, In Vitro, and In Vivo Anticancer Evaluation. ACS Pharmacol Transl Sci 2020; 3:965-977. [PMID: 33073194 DOI: 10.1021/acsptsci.0c00096] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Indexed: 01/10/2023]
Abstract
Several thiophene featuring compounds are known for their promising antiproliferative activity. Prompted by the urgent need to identify new potent anticancer agents, 16 compounds of benzamides, benzylamines, and urea analogues incorporating a cyclohepta[b]thiophene scaffold were synthesized and biologically evaluated with a cell proliferation assay using the A549 nonsmall cell lung cancer cell line. Compound 17 demonstrated both potent and broad-spectrum anticancer activity with submicromolar 50% growth inhibition (GI50) values. It also showed superior antiproliferative activity (vs nocodazole) in OVACAR-4, OVACAR-5, CAKI-1, and T47D cell lines with GI50 values of 2.01 (vs 22.28), 2.27 (vs 20.75), 0.69 (vs 1.11), and 0.362 (vs 81.283) μM, respectively. Additionally, compound 17 displayed minimal cytotoxicity based on 50% lethal concentration (LC50) values toward all tested cell lines. Further cell-based mechanistic studies of compound 17 revealed its ability to induce cell cycle arrest of A549 cells as evidenced by dose dependent G2/M accumulation. Furthermore, induction of early apoptosis along with activation of caspase 3, 8, and 9 were confirmed in A549 cells treated with compound 17. Targeting tubulin polymerization may explain the mechanism of the antiproliferative activity of compound 17 based on cell cycle analysis, detected apoptosis, and in vitro inhibition of tubulin polymerization. In vitro data were further supported by in vivo antitumor efficacy studies of compound 17 in a CT26 murine model for which the results showed a reduction in the tumor growth compared to untreated mice. Overall, compound 17 has the potential to function as a promising candidate for further development of potent anticancer chemotherapeutics.
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Affiliation(s)
- Somaya A Abdel-Rahman
- Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, Iowa 52242, United States.,Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt
| | - Ashraf K El-Damasy
- Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt
| | - Ghada S Hassan
- Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt
| | - Emad I Wafa
- Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, Iowa 52242, United States
| | - Sean M Geary
- Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, Iowa 52242, United States
| | - Azza R Maarouf
- Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt
| | - Aliasger K Salem
- Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, Iowa 52242, United States
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Yi Y, Fang Y, Wu K, Liu Y, Zhang W. Comprehensive gene and pathway analysis of cervical cancer progression. Oncol Lett 2020; 19:3316-3332. [PMID: 32256826 PMCID: PMC7074609 DOI: 10.3892/ol.2020.11439] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Accepted: 01/15/2020] [Indexed: 12/15/2022] Open
Abstract
Cervical Cancer is one of the leading causes of cancer-associated mortality in women. The present study aimed to identify key genes and pathways involved in cervical cancer (CC) progression, via a comprehensive bioinformatics analysis. The GSE63514 dataset from the Gene Expression Omnibus database was analyzed for hub genes and cancer progression was divided into four phases (phases I-IV). Pathway enrichment, protein-protein interaction (PPI) and pathway crosstalk analyses were performed, to identify key genes and pathways using a criterion nodal degree ≥5. Gene pathway analysis was determined by mapping the key genes into the key pathways. Co-expression between key genes and their effect on overall survival (OS) time was assessed using The Cancer Genome Atlas database. A total of 3,446 differentially expressed genes with 107 hub genes were identified within the four phases. A total of 14 key genes with 11 key pathways were obtained, following extraction of ≥5 degree nodes from the PPI and pathway crosstalk networks. Gene pathway analysis revealed that CDK1 and CCNB1 regulated the cell cycle and were activated in phase I. Notably, the following terms, 'pathways in cancer', 'focal adhesion' and the 'PI3K-Akt signaling pathway' ranked the highest in phases II-IV. Furthermore, FN1, ITGB1 and MMP9 may be associated with metastasis of tumor cells. STAT1 was indicated to predominantly function at the phase IV via cancer-associated signaling pathways, including 'pathways in cancer' and 'Toll-like receptor signaling pathway'. Survival analysis revealed that high ITGB1 and FN1 expression levels resulted in significantly worse OS. CDK1 and CCNB1 were revealed to regulate proliferation and differentiation through the cell cycle and viral tumorigenesis, while FN1 and ITGB1, which may be developed as novel prognostic factors, were co-expressed to induce metastasis via cancer-associated signaling pathways, including PI3K-Art signaling pathway, and focal adhesion in CC; however, the underlying molecular mechanisms require further research.
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Affiliation(s)
- Yuexiong Yi
- Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Yan Fang
- Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Kejia Wu
- Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Yanyan Liu
- Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Wei Zhang
- Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
- Correspondence to: Professor Wei Zhang, Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, Hubei 430071, P.R. China, E-mail:
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Titanium Dioxide Nanoparticles: Prospects and Applications in Medicine. NANOMATERIALS 2020; 10:nano10020387. [PMID: 32102185 PMCID: PMC7075317 DOI: 10.3390/nano10020387] [Citation(s) in RCA: 247] [Impact Index Per Article: 49.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/04/2020] [Revised: 02/19/2020] [Accepted: 02/19/2020] [Indexed: 01/26/2023]
Abstract
Metallic and metal oxide nanoparticles (NPs), including titanium dioxide NPs, among polymeric NPs, liposomes, micelles, quantum dots, dendrimers, or fullerenes, are becoming more and more important due to their potential use in novel medical therapies. Titanium dioxide (titanium(IV) oxide, titania, TiO2) is an inorganic compound that owes its recent rise in scientific interest to photoactivity. After the illumination in aqueous media with UV light, TiO2 produces an array of reactive oxygen species (ROS). The capability to produce ROS and thus induce cell death has found application in the photodynamic therapy (PDT) for the treatment of a wide range of maladies, from psoriasis to cancer. Titanium dioxide NPs were studied as photosensitizing agents in the treatment of malignant tumors as well as in photodynamic inactivation of antibiotic-resistant bacteria. Both TiO2 NPs themselves, as well as their composites and combinations with other molecules or biomolecules, can be successfully used as photosensitizers in PDT. Moreover, various organic compounds can be grafted on TiO2 nanoparticles, leading to hybrid materials. These nanostructures can reveal increased light absorption, allowing their further use in targeted therapy in medicine. In order to improve efficient anticancer and antimicrobial therapies, many approaches utilizing titanium dioxide were tested. Results of selected studies presenting the scope of potential uses are discussed in this review.
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25
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Fröhlich T, Ndreshkjana B, Muenzner JK, Reiter C, Hofmeister E, Mederer S, Fatfat M, El-Baba C, Gali-Muhtasib H, Schneider-Stock R, Tsogoeva SB. Synthesis of Novel Hybrids of Thymoquinone and Artemisinin with High Activity and Selectivity Against Colon Cancer. ChemMedChem 2017; 12:226-234. [PMID: 27973725 DOI: 10.1002/cmdc.201600594] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2016] [Indexed: 12/28/2022]
Abstract
Colorectal cancer causes 0.5 million deaths each year. To combat this type of cancer the development of new specific drug candidates is urgently needed. In the present work seven novel thymoquinone-artemisinin hybrids with different linkers were synthesized and tested for their in vitro anticancer activity against a panel of various tumor cell lines. The thymoquinone-artesunic acid hybrid 7 a, in which both subunits are connected via an ester bond, was found to be the most active compound and selectively decreased the viability of colorectal cancer cells with an IC50 value of 2.4 μm (HCT116) and 2.8 μm (HT29). Remarkably, hybrid 7 a was up to 20-fold more active than its parent compounds (thymoquinone and artesunic acid), while not affecting nonmalignant colon epithelial HCEC cells (IC50 >100 μm). Moreover, the activity of hybrid 7 a was superior to that of various 1:1 mixtures of thymoquinone and artesunic acid. Furthermore, hybrid 7 a was even more potent against both colon cancer cell lines than the clinically used drug 5-fluorouracil. These results are another excellent proof of the hybridization concept and confirm that the type and length of the linker play a crucial role for the biological activity of a hybrid drug. Besides an increase in reactive oxygen species (ROS), elevated levels of the DNA-damage marker γ-H2AX were observed. Both effects seem to be involved in the molecular mechanism of action for hybrid 7 a in colorectal cancer cells.
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Affiliation(s)
- Tony Fröhlich
- Organic Chemistry Chair I and Interdisciplinary Center for Molecular Materials (ICMM), Friedrich Alexander University of Erlangen-Nürnberg, Henkestr. 42, 91054, Erlangen, Germany
| | - Benardina Ndreshkjana
- Experimental Tumor Pathology, Institute of Pathology, Friedrich Alexander University of Erlangen-Nürnberg, Universitätsstr. 22, 91054, Erlangen, Germany
| | - Julienne K Muenzner
- Experimental Tumor Pathology, Institute of Pathology, Friedrich Alexander University of Erlangen-Nürnberg, Universitätsstr. 22, 91054, Erlangen, Germany
| | - Christoph Reiter
- Organic Chemistry Chair I and Interdisciplinary Center for Molecular Materials (ICMM), Friedrich Alexander University of Erlangen-Nürnberg, Henkestr. 42, 91054, Erlangen, Germany
| | - Elisabeth Hofmeister
- Organic Chemistry Chair I and Interdisciplinary Center for Molecular Materials (ICMM), Friedrich Alexander University of Erlangen-Nürnberg, Henkestr. 42, 91054, Erlangen, Germany
| | - Sandra Mederer
- Experimental Tumor Pathology, Institute of Pathology, Friedrich Alexander University of Erlangen-Nürnberg, Universitätsstr. 22, 91054, Erlangen, Germany
| | - Maamoun Fatfat
- Department of Biology, Department of Anatomy, Cell Biology and Physiological Science, American University of Beirut, Beirut, Lebanon
| | - Chirine El-Baba
- Experimental Tumor Pathology, Institute of Pathology, Friedrich Alexander University of Erlangen-Nürnberg, Universitätsstr. 22, 91054, Erlangen, Germany
| | - Hala Gali-Muhtasib
- Department of Biology, Department of Anatomy, Cell Biology and Physiological Science, American University of Beirut, Beirut, Lebanon
| | - Regine Schneider-Stock
- Experimental Tumor Pathology, Institute of Pathology, Friedrich Alexander University of Erlangen-Nürnberg, Universitätsstr. 22, 91054, Erlangen, Germany
| | - Svetlana B Tsogoeva
- Organic Chemistry Chair I and Interdisciplinary Center for Molecular Materials (ICMM), Friedrich Alexander University of Erlangen-Nürnberg, Henkestr. 42, 91054, Erlangen, Germany
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Jassbi AR, Zare S, Firuzi O, Xiao J. Bioactive phytochemicals from shoots and roots of Salvia species. PHYTOCHEMISTRY REVIEWS 2016; 15:829-867. [DOI: 10.1007/s11101-015-9427-z] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
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Ait-Belkacem R, Berenguer C, Villard C, Ouafik L, Figarella-Branger D, Beck A, Chinot O, Lafitte D. Monitoring therapeutic monoclonal antibodies in brain tumor. MAbs 2015; 6:1385-93. [PMID: 25484065 DOI: 10.4161/mabs.34405] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Bevacizumab induces normalization of abnormal blood vessels, making them less leaky. By binding to vascular endothelial growth factor, it indirectly attacks the vascular tumor mass. The optimal delivery of targeted therapies including monoclonal antibodies or anti-angiogenesis drugs to the target tissue highly depends on the blood-brain barrier permeability. It is therefore critical to investigate how drugs effectively reach the tumor. In situ investigation of drug distribution could provide a better understanding of pharmacological agent action and optimize chemotherapies for solid tumors. We developed an imaging method coupled to protein identification using matrix-assisted laser desorption/ionization mass spectrometry. This approach monitored bevacizumab distribution within the brain structures, and especially within the tumor, without any labeling.
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Key Words
- 5 DAN, 1
- 5-diaminonaphtalene
- BBB, blood-brain barrier
- CRC, metastatic colorectal cancer
- CSF, cerebrospinal fluid; 1
- EMA, European Medicines Agency
- FDA, Food and Drug Administration
- GBM, glioblastoma multiforme
- IMS, imaging mass spectrometry
- ISD, in-source decay
- ITO, indium tin oxide
- LC-MS/MS, liquid chromatography coupled to tandem mass spectrometry
- MALDI imaging mass spectrometry
- MALDI, matrix-assisted laser desorption/ionization
- NSCLC, non-small cell lung cancer
- RMS, root mean square
- RP-HPLC, reversed phase high-performance liquid chromatography
- TOF, time of flight
- VEGF, vascular endothelial growth factor
- VEGFR, vascular endothelial growth factor receptor
- VH, variable domain of the heavy chain
- VL, variable domain of the light chain
- WHO, world health organization
- bevacizumab
- glioblastoma multiforme
- mAbs, monoclonal antibodies
- monoclonal antibodies
- pE, pyroglutamate
- palivizumab
- top down in source decay
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Affiliation(s)
- Rima Ait-Belkacem
- a Aix-Marseille Université Inserm ; CRO2 UMR S-911; Marseille , France
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Wang XJ, Li Y, Luo L, Wang H, Chi Z, Xin A, Li X, Wu J, Tang X. Oxaliplatin activates the Keap1/Nrf2 antioxidant system conferring protection against the cytotoxicity of anticancer drugs. Free Radic Biol Med 2014; 70:68-77. [PMID: 24556415 DOI: 10.1016/j.freeradbiomed.2014.02.010] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2013] [Revised: 01/30/2014] [Accepted: 02/09/2014] [Indexed: 12/21/2022]
Abstract
Oxaliplatin is an important drug in the treatment of advanced metastatic colorectal cancer. NF-E2 p45-related factor 2 (Nrf2) is a key transcription factor that controls genes encoding cytoprotective and detoxifying enzymes through antioxidant-response elements (AREs) in their regulatory regions. Here, we report that oxaliplatin is an activator of the Nrf2 signaling pathway, with upregulation of ARE-driven genes and glutathione elevation. An injection of oxaliplatin into mice enhanced the expression of glutathione transferases and antioxidant enzymes in the small and large intestines of wild-type (WT) mice but not Nrf2(-/-) mice, indicating that oxaliplatin activates Nrf2 in vivo. Oxaliplatin failed to increase Nrf2 accumulation in non-small-cell lung cancer A549 cells, which harbor a dysfunctional somatic mutation of KEAP1. However, forced expression of WT mKeap1 restored the ability of oxaliplatin to activate the transcription factor. Cys(151) in Keap1 was required for the response stimulated by oxaliplatin. In addition, dichloro(1,2-diaminocyclohexane) platinum, a metabolite of oxaliplatin, was found to have the same effect in activating the ARE-gene battery as its parent drug, whereas another metabolite, oxalate, was ineffective. Moreover, two other platinum derivatives, cisplatin and carboplatin, had no effect on the Keap1/Nrf2 system. Furthermore, activation of Nrf2 by oxaliplatin reduced the sensitivity of colon cancer cells to therapeutic drugs. Conversely, knockdown of Nrf2 by Nrf2 siRNA reduced oxaliplatin-induced chemoresistance. Our study showed that oxaliplatin exerts protection against the cytotoxicity of anticancer drugs via Nrf2, indicating an important role of Nrf2 in oxaliplatin-based chemotherapy.
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Affiliation(s)
- Xiu Jun Wang
- Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058, People׳s Republic of China.
| | - Yinyan Li
- Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058, People׳s Republic of China
| | - Lin Luo
- Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058, People׳s Republic of China
| | - Hongyan Wang
- Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058, People׳s Republic of China; Department of Biochemistry and Genetics,School of Medicine, Zhejiang University, Hangzhou 310058, People׳s Republic of China
| | - Zhexu Chi
- Department of Biochemistry and Genetics,School of Medicine, Zhejiang University, Hangzhou 310058, People׳s Republic of China
| | - Ai Xin
- Department of Biochemistry and Genetics,School of Medicine, Zhejiang University, Hangzhou 310058, People׳s Republic of China
| | - Xin Li
- Department of Biochemistry and Genetics,School of Medicine, Zhejiang University, Hangzhou 310058, People׳s Republic of China
| | - Jiaguo Wu
- Division of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310058, People׳s Republic of China
| | - Xiuwen Tang
- Department of Biochemistry and Genetics,School of Medicine, Zhejiang University, Hangzhou 310058, People׳s Republic of China.
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Novel artemisinin derivatives with potential usefulness against liver/colon cancer and viral hepatitis. Bioorg Med Chem 2013; 21:4432-41. [DOI: 10.1016/j.bmc.2013.04.059] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2013] [Revised: 04/12/2013] [Accepted: 04/18/2013] [Indexed: 12/18/2022]
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30
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Herraez E, Gonzalez-Sanchez E, Vaquero J, Romero MR, Serrano MA, Marin JJG, Briz O. Cisplatin-induced chemoresistance in colon cancer cells involves FXR-dependent and FXR-independent up-regulation of ABC proteins. Mol Pharm 2012; 9:2565-76. [PMID: 22800197 DOI: 10.1021/mp300178a] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Export pumps often limit the usefulness of anticancer drugs. Here we investigated the effect of cisplatin on the expression of ABC proteins in human colon cancer cells. Short-term incubation of Caco-2 and LS174T cells with cisplatin resulted in up-regulation of several ABC pumps, in particular MRP2 and BCRP. In partially cisplatin-resistant cells (LS174T/R) obtained by long-term exposure to cisplatin, MRP2 and BCRP up-regulation was more marked. This was further enhanced when these cells were cultured under maintained stimulation with cisplatin. The MRP2 promoter (MRP2pr) was cloned, and partially deleted constructs linked to reporter genes were generated. Transfection of LS174T and LS174T/R cells with these constructs revealed the ability of cisplatin to activate MRP2pr. The intensity of this response was dependent on the conserved MRP2pr region. Basal MRP2pr activity was higher in LS174T/R cells, in which the expression of the transcription factors c/EBPβ, HNF1α, HNF3β, and HNF4α, but not PXR, p53, c-Myc, AP1, YB-1, NRF2, and RARα was enhanced. Up-regulation was particularly high for FXR (200-fold) and SHP (50-fold). In LS174T/R cells, GW4064 induced the expression of FGF19, SHP, OSTα/β, but not MRP2 and BCRP, although the sensitivity of these cells to cisplatin was further reduced. In LS174T cells, GW4064-induced chemoresistance was seen only after being transfected with FXR+RXR, when BCRP, but not MRP2, was up-regulated. Protection of LS174T cells against cisplatin was mimicked by transfection with BCRP. In conclusion, in colon cancer cells, cisplatin treatment enhances chemoresistance through FXR-dependent and FXR-independent mechanisms involving the expression of BCRP and MRP2, respectively.
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Affiliation(s)
- Elisa Herraez
- Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), Biomedical Research Institute of Salamanca, University of Salamanca, Spain
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Zhang D, Fan D. New insights into the mechanisms of gastric cancer multidrug resistance and future perspectives. Future Oncol 2010; 6:527-37. [PMID: 20373867 DOI: 10.2217/fon.10.21] [Citation(s) in RCA: 85] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer is still the second leading cause of cancer death worldwide. Chemotherapy is one of the major treatment options for advanced gastric cancer. The efficacy of chemotherapy for gastric cancer is poor due to insensitivity and the development of multidrug resistance (MDR). Gastric cancer MDR involves a large number of molecules and complex mechanisms. Classical drug-resistant molecules, such as P-glycoprotein/ABCB1 and MRP1/ABCC1, have been found to play important roles in mediating MDR in some gastric cancers. In recent years, new molecules and mechanisms have been found to be associated with the development of gastric cancer MDR and might provide new targets for tackling gastric cancer MDR. Combined use of molecularly targeted therapy with chemotherapy may offer improved outcomes for gastric cancer patients and might provide new threads of hope for gastric cancer treatment.
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Affiliation(s)
- Dexin Zhang
- State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Disease, Fourth Military Medical University, 15 West Chang-Le Road, Xi'an 710032, People's Republic of China.
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